Colorectal Cancer

1. Clinical Overview

Summary

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide and the second leading cause of cancer-related mortality, accounting for approximately 935,000 deaths annually.[1] It arises predominantly from the epithelium of the colon or rectum through a well-characterized multistep process known as the adenoma-carcinoma sequence. Approximately 90% of colorectal cancers are adenocarcinomas, with the remainder comprising rare histological variants including mucinous, signet-ring cell, and neuroendocrine tumours.[2]

The disease demonstrates significant geographical variation in incidence, with highest rates observed in developed countries, reflecting the impact of dietary factors, sedentary lifestyle, and increased longevity.[3] Major risk factors include advancing age (median diagnosis at 68 years), family history of colorectal cancer or adenomatous polyps, hereditary cancer syndromes (Lynch syndrome, Familial Adenomatous Polyposis), inflammatory bowel disease (particularly long-standing ulcerative colitis), and modifiable lifestyle factors including obesity, physical inactivity, consumption of red and processed meats, smoking, and excessive alcohol intake.[4]

Population-based screening programmes utilizing faecal immunochemical testing (FIT) have demonstrated substantial mortality reduction through early detection of cancer and removal of premalignant polyps.[5] The UK NHS Bowel Cancer Screening Programme, extended in 2021 to include individuals aged 50-74 years (previously 60-74), exemplifies evidence-based preventive strategy implementation at scale.

Diagnosis requires colonoscopic visualization with histological confirmation via biopsy. Staging employs the TNM (Tumour-Node-Metastasis) classification system and necessitates contrast-enhanced CT of chest, abdomen, and pelvis for metastatic disease assessment. Rectal cancers additionally require high-resolution MRI pelvis for local staging, particularly to evaluate circumferential resection margin (CRM) involvement and extramural vascular invasion (EMVI), which critically inform neoadjuvant treatment decisions.[6]

Treatment is fundamentally stage-dependent and coordinated through multidisciplinary team (MDT) discussion. Localized disease (Stages I-III) is managed with curative intent primarily through surgical resection, with adjuvant chemotherapy administered to node-positive (Stage III) disease and selected high-risk Stage II cases. Locally advanced rectal cancers benefit from neoadjuvant chemoradiotherapy or short-course radiotherapy prior to definitive surgery, which has significantly reduced local recurrence rates.[7] Metastatic disease (Stage IV) requires systemic chemotherapy, often combined with targeted biological agents (bevacizumab, cetuximab, panitumumab) based on tumour molecular profiling. Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumours demonstrate exceptional responsiveness to immune checkpoint inhibitors, establishing a paradigm shift in treatment selection.[8]

Five-year survival ranges from > 90% for Stage I disease to approximately 14% for Stage IV, underscoring the critical importance of early detection and the devastating impact of metastatic spread.[9]

Key Facts

• Global Burden: 3rd most common cancer; > 1.9 million new cases annually worldwide[1]
• UK Incidence: ~42,000 new diagnoses/year; 4th most common malignancy
• Mortality: 2nd leading cause of cancer death globally (~935,000 deaths/year)[1]
• Lifetime Risk: ~1 in 15 men, ~1 in 18 women in developed countries
• Peak Age: 65-75 years; less than 5% occur before age 40 (excluding hereditary syndromes)
• Adenoma-Carcinoma Sequence: 10-15 year progression; provides screening window[2]
• Screening Impact: FIT-based programmes reduce CRC mortality by 16%[5]
• Anatomical Distribution: 40% distal colon/rectum, 40% proximal colon, 20% other
• Left vs Right: Left-sided tumours (descending, sigmoid, rectum) more symptomatic earlier; right-sided (caecum, ascending) often present with anaemia
• Rectal Cancer: Comprises ~30% of CRC; requires MRI staging and neoadjuvant therapy consideration[6]
• Staging Determines Treatment: Stage I-II surgery alone; Stage III adjuvant chemotherapy; Stage IV palliative systemic therapy ± metastasectomy
• Adjuvant Chemotherapy: FOLFOX (5-FU/leucovorin/oxaliplatin) standard for Stage III; improves 5-year disease-free survival by 7.5%[10]
• MSI-H Tumours: 15% of CRCs; better prognosis; respond to pembrolizumab immunotherapy[8]
• 5-Year Survival: Stage I 92%, Stage II 82%, Stage III 67%, Stage IV 14%[9]
• Total Mesorectal Excision (TME): Surgical gold standard for rectal cancer; reduced local recurrence from 30% to less than 10%[11]

Clinical Pearls

"Right-Sided = Silent Killer, Left-Sided = Symptomatic Sentinel": Right-sided colon cancers (caecum, ascending colon) have wider luminal diameter and liquid stool content, allowing tumours to grow large before causing symptoms. Presentation is typically insidious with iron deficiency anaemia, weight loss, and occasionally a palpable mass. Left-sided cancers (descending, sigmoid, rectum) encounter formed stool in narrower lumen, causing obstructive symptoms (change in bowel habit, constipation, tenesmus) and visible rectal bleeding earlier in disease course.

"FIT Saves Lives — The Gatekeeper to Colonoscopy": The Faecal Immunochemical Test (FIT) quantitatively measures haemoglobin concentration in stool using antibodies specific to human globin. Unlike older guaiac-based tests, FIT does not require dietary restriction, demonstrates superior sensitivity (79%) and specificity (94%) for CRC, and enables threshold adjustment.[5] A positive FIT (≥10 μg Hb/g faeces in NHS screening) mandates colonoscopy. Implementation of FIT-based screening has shifted stage distribution toward earlier disease and reduced CRC mortality by 16% in screened populations.

"MRI Pelvis Before Rectal Surgery — The CRM Is King": Rectal cancer staging fundamentally differs from colon cancer due to anatomical constraints of the bony pelvis and absence of serosa, making local recurrence historically problematic. High-resolution MRI pelvis is mandatory to assess tumour height from anal verge, depth of invasion (T stage), nodal involvement, circumferential resection margin (CRM) status, and extramural vascular invasion (EMVI).[6] A threatened or involved CRM (less than 1mm from mesorectal fascia) predicts positive margin after surgery and mandates neoadjuvant chemoradiotherapy to downstage tumour and enable curative resection. MRI accuracy for CRM prediction exceeds 90%.

"Lynch Syndrome: Test All Tumours, Find the Families": Universal tumour testing for mismatch repair deficiency (immunohistochemistry for MLH1, MSH2, MSH6, PMS2) or microsatellite instability (MSI) should be performed on all newly diagnosed CRCs regardless of age.[12] Approximately 3% of CRCs represent Lynch syndrome (hereditary nonpolyposis colorectal cancer), an autosomal dominant condition conferring 50-80% lifetime CRC risk. Identifying Lynch syndrome enables cascade genetic testing of at-risk relatives and implementation of intensive surveillance, reducing cancer incidence and mortality. MSI-H tumours, whether germline (Lynch) or sporadic (MLH1 promoter hypermethylation), demonstrate better prognosis and exceptional response to immune checkpoint inhibitors (pembrolizumab, nivolumab).[8]

"TME: Planes, Not Lines — Surgical Precision Prevents Recurrence": Total Mesorectal Excision (TME), pioneered by Bill Heald in the 1980s, revolutionized rectal cancer surgery by recognizing the mesorectum as the primary site of local tumour spread and lymphatic drainage. TME involves precise dissection in the avascular "holy plane" between mesorectal fascia and parietal pelvic fascia, removing the rectum with intact mesorectal envelope en bloc.[11] This anatomically-based approach reduced local recurrence from 30-40% (pre-TME era) to less than 10% when combined with neoadjuvant therapy, and is now the global surgical standard. Quality indicators include intact mesorectal envelope, negative CRM, and ≥12 lymph nodes harvested.

"Oncogenes Drive the Journey: APC → KRAS → TP53": The Vogelstein model of colorectal carcinogenesis describes stepwise accumulation of genetic alterations over 10-15 years.[2] Initial mutation in APC (adenomatous polyposis coli) tumour suppressor gene disrupts Wnt signalling, initiating adenoma formation. Activating KRAS mutations drive adenoma growth and progression to high-grade dysplasia. Loss of TP53 function enables malignant transformation to invasive carcinoma. This molecular understanding underpins screening strategies (exploiting the long lead time), targeted therapies (anti-EGFR agents only effective in RAS wild-type tumours), and prognostication.

Why This Matters Clinically

Colorectal cancer represents a quintessential "preventable yet deadly" malignancy. Every clinician must master recognition of red flag symptoms and appropriate urgency of referral under 2-week wait pathways, as 25% of patients present with emergency complications (obstruction, perforation, bleeding) associated with worse outcomes. Understanding screening programmes and polyp surveillance guidelines enables risk stratification and prevention. Competence in interpreting staging investigations, particularly MRI pelvis for rectal cancer, ensures appropriate MDT discussion and treatment sequencing. Knowledge of molecular subtypes (RAS status, MSI-H) is essential for contemporary systemic therapy selection. Finally, familiarity with surgical approaches (TME for rectal cancer, extent of colonic resection) and adjuvant treatment indications enables informed prognostic discussion with patients facing a diagnosis that, despite advances, still claims 16,500 lives annually in the UK alone.

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2. Epidemiology

Global and Regional Incidence

Colorectal cancer demonstrates marked geographical heterogeneity in incidence and mortality, reflecting variations in dietary patterns, screening uptake, healthcare infrastructure, and genetic susceptibility.[1,3]

Highest Incidence Regions (Age-standardized rate > 40 per 100,000):

• Australia and New Zealand (highest globally)
• Western Europe (particularly Netherlands, Denmark, Norway)
• North America (USA, Canada)
• Eastern Europe (Czech Republic, Hungary, Slovakia)
• Developed East Asia (South Korea, Japan, Singapore)

Lowest Incidence Regions (Age-standardized rate less than 10 per 100,000):

• Sub-Saharan Africa (except South Africa)
• South-Central Asia (India, Pakistan, Bangladesh)
• Western Africa

UK-Specific Data:

Temporal Trends

Overall Incidence: Age-standardized incidence rates in developed countries have stabilized or modestly declined since 2000, attributed to widespread screening implementation and polyp removal.[5] However, concerning increases in early-onset CRC (age less than 50) have been observed globally, with incidence rising by 1-2% annually since 1990.[13] Proposed contributors include obesity epidemic, dietary changes, gut microbiome alterations, and antibiotic exposure, though definitive causation remains unclear.

Mortality: CRC mortality has declined substantially in screening-participating populations (15-30% reduction), reflecting both stage migration (earlier diagnosis) and improved treatment.[5] The UK has experienced a 30% mortality reduction since the early 1990s despite stable incidence, demonstrating the combined impact of screening and therapeutic advances.

Age and Sex Distribution

Age: CRC risk increases exponentially with age, doubling each decade after age 40. More than 90% of cases occur in individuals over 50 years, justifying the age threshold for population screening. However, early-onset CRC (age less than 50) now accounts for 10-12% of diagnoses and represents a growing public health concern.[13]

Sex: Males demonstrate 25% higher incidence than females, potentially reflecting hormonal protection in premenopausal women (oestrogen may be protective) and higher prevalence of risk factors (smoking, obesity, red meat consumption) in men.

Risk Factors

Non-Modifiable Risk Factors

Modifiable Risk Factors

Protective Factors

• Aspirin (regular use > 5 years): 20-30% risk reduction; USPSTF recommends low-dose aspirin for CRC prevention in selected high-risk individuals aged 50-59[16]
• Dietary fibre: 10% risk reduction per 10g/day increase
• Physical activity: 20-30% risk reduction with regular moderate-vigorous activity
• Calcium supplementation: Modest protective effect (10-15% reduction)
• Vitamin D: Observational association (higher serum 25-OH vitamin D correlates with lower CRC risk); RCTs inconclusive
• NSAIDs (non-aspirin): COX-2 inhibitors demonstrate chemopreventive effect but cardiovascular toxicity limits use

Hereditary Syndromes

Lynch Syndrome Specifics: Most common hereditary CRC syndrome (~3% of all CRCs). Caused by germline mutations in DNA mismatch repair (MMR) genes. Amsterdam II criteria and revised Bethesda guidelines identify families for testing.[12] Universal tumour screening (IHC for MMR proteins or MSI testing) recommended for all newly diagnosed CRCs to identify probands. Cumulative CRC risk by age 70: MLH1/MSH2 (46-61%), MSH6 (17-29%), PMS2 (13-20%). Also increased risk of endometrial (30-60%), ovarian, gastric, small bowel, urothelial, and sebaceous carcinomas. Surveillance colonoscopy every 1-2 years from age 25 (or 5 years before youngest family diagnosis) reduces mortality by 60%.

Inflammatory Bowel Disease

Chronic inflammation promotes carcinogenesis through oxidative DNA damage, aberrant methylation, and dysplasia-carcinoma sequence. CRC risk factors in IBD include:[15]

• Disease duration: Risk negligible less than 8 years, increases ~0.5-1% per year thereafter
• Disease extent: Pancolitis > left-sided > proctitis
• Severity of inflammation: Persistent active inflammation
• Concomitant primary sclerosing cholangitis: 4-fold increased risk in UC
• Family history of CRC: Independent additional risk
• Young age at IBD diagnosis: Longer cumulative exposure

British Society of Gastroenterology recommends surveillance colonoscopy beginning 8-10 years after symptom onset, with interval determined by risk stratification (high-risk: annual; intermediate: 2-3 years; low-risk: 5 years).

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3. Pathophysiology

Molecular Pathogenesis: Three Pathways to Cancer

Colorectal cancer develops through at least three distinct molecular pathways, each characterized by specific genetic and epigenetic alterations.[2,17]

1. Chromosomal Instability (CIN) Pathway (70-85% of CRCs)

The classical adenoma-carcinoma sequence, described by Vogelstein in 1990, accounts for the majority of sporadic CRCs.[2]

Sequence of Events:

Step 1: Initiation — Normal Epithelium to Small Adenoma

• APC inactivation (first hit): Germline in FAP, somatic in sporadic
• APC function: Negative regulator of Wnt/β-catenin signalling pathway
• Result: Constitutive Wnt activation → uncontrolled cellular proliferation → adenoma formation
• Histology: Tubular or tubulovillous adenoma, low-grade dysplasia

Step 2: Promotion — Small to Large Adenoma

• KRAS activation (~40% of adenomas): Oncogene mutation (codons 12, 13, 61)
• KRAS function: RAS-MAPK pathway activation driving cell growth
• Result: Adenoma growth and progression to high-grade dysplasia
• Size correlation: Larger adenomas more likely harbour KRAS mutations

Step 3: Progression — High-Grade Dysplasia to Invasive Carcinoma

• TP53 inactivation (~50-70% of CRCs): Loss of chromosome 17p
• TP53 function: "Guardian of the genome" — cell cycle checkpoint, apoptosis
• Result: Genomic instability, resistance to apoptosis → invasive carcinoma
• Additional alterations: SMAD4 loss (18q deletion), PI3K activation

Step 4: Metastasis

• Additional mutations enable epithelial-mesenchymal transition (EMT)
• Angiogenesis (VEGF upregulation)
• Invasion through basement membrane → lymphovascular invasion → metastasis

Timeline: 10-15 years from initiating mutation to invasive cancer, providing substantial screening window. However, some "aggressive" adenomas may progress more rapidly.

2. Microsatellite Instability (MSI) Pathway (15% of CRCs)

Mechanism: Defective DNA mismatch repair (MMR) system fails to correct replication errors in repetitive DNA sequences (microsatellites), leading to accumulation of mutations, particularly in coding regions with repeat sequences.[12]

Causes of MMR Deficiency:

• Germline MMR mutation (Lynch syndrome): 3% of all CRCs
  • MLH1, MSH2, MSH6, PMS2 mutations
  • Autosomal dominant inheritance
  • Early onset (median age 45 vs 68 in sporadic)
• Sporadic MLH1 promoter hypermethylation: 12% of all CRCs
  • Epigenetic silencing of MLH1
  • Associated with BRAF V600E mutation
  • Older age, right-sided location, female predominance

Tumour Characteristics:

• Right-sided predominance (caecum, ascending colon)
• Poor differentiation, mucinous or signet-ring cell histology
• Tumour-infiltrating lymphocytes (immune-rich microenvironment)
• Crohn's-like lymphocytic reaction
• Synchronous and metachronous tumours more common

Clinical Significance:

• Better prognosis: MSI-H Stage II/III CRCs have superior survival vs MSS
• No benefit from 5-FU adjuvant chemotherapy: Stage II MSI-H may not require adjuvant therapy
• Response to immunotherapy: PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab) highly effective due to high tumour mutational burden generating neoantigens[8]

Testing: Performed via immunohistochemistry (IHC) for MMR proteins (loss of expression indicates dMMR) or PCR-based MSI testing. Universal testing of all newly diagnosed CRCs recommended to identify Lynch syndrome.

3. CpG Island Methylator Phenotype (CIMP) Pathway (20-30% of CRCs)

Mechanism: Widespread hypermethylation of CpG islands in gene promoter regions, leading to transcriptional silencing of tumour suppressor genes without DNA sequence mutation.[17]

Molecular Features:

• CIMP-high: Associated with BRAF V600E mutation, MLH1 silencing (MSI-H), right-sided
• CIMP-low: Intermediate methylation, KRAS mutations common

Serrated Pathway: CIMP-associated cancers often arise from serrated polyps (sessile serrated lesions, traditional serrated adenomas) rather than conventional adenomas. This pathway may progress more rapidly than adenoma-carcinoma sequence, with potential for accelerated carcinogenesis.

Anatomical Patterns and Clinical Correlation

Right-Sided Tumours: Caecum and ascending colon have larger luminal diameter accommodating bulky, fungating masses that rarely obstruct. Liquid stool consistency and occult bleeding lead to iron deficiency anaemia as presenting feature. Right-sided CRCs more frequently harbor MSI-H, BRAF mutations, and demonstrate CIMP-high phenotype. Some data suggest worse prognosis stage-for-stage compared to left-sided, possibly due to biology rather than delayed detection.

Left-Sided Tumours: Descending and sigmoid colon have narrower lumen with formed stool, leading to obstructive symptoms (constipation, change in bowel habit, colicky pain) and overt rectal bleeding relatively early. More commonly demonstrate CIN pathway with KRAS mutations. Better prognosis than right-sided, particularly in metastatic setting where left-sided primaries show superior outcomes with anti-EGFR therapy.

Rectal Tumours: Unique anatomical considerations include lack of serosal covering (replaced by mesorectal fascia), proximity to pelvic autonomic nerves (sexual/urinary function), and anal sphincter complex. Local spread to mesorectal lymph nodes and potential for circumferential margin involvement necessitate neoadjuvant therapy and TME surgery.

Mechanisms of Spread

Local Invasion: Progressive infiltration through bowel wall layers (mucosa → submucosa → muscularis propria → serosa/mesorectal fascia) defines T stage. Invasion of adjacent structures (bladder, uterus, prostate, pelvic sidewall) indicates T4b disease requiring multivisceral resection.

Lymphatic Spread: Sequential involvement of pericolic/perirectal nodes (N1 a: 1 node, N1 b: 2-3 nodes) → intermediate nodes along named vessels (N1 c: tumour deposits without nodes) → apical nodes at vascular origin (N2 a: 4-6 nodes, N2 b: ≥7 nodes). Extent of nodal involvement powerfully predicts prognosis and determines adjuvant treatment.

Haematogenous Spread: Portal venous drainage preferentially delivers colonic tumour cells to liver (most common metastatic site, 50-70% of metastatic patients). Rectal venous drainage via systemic circulation increases lung metastasis incidence (40%). Other sites: peritoneum (20%), bones (10%), brain (3%).

Transperitoneal Spread: Tumours penetrating serosa may seed peritoneal surface, causing peritoneal carcinomatosis with malignant ascites. Particularly common with perforated tumours, mucinous histology, and ovarian involvement (Krukenberg tumour).

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4. Clinical Presentation

Symptom Patterns by Anatomical Location

The clinical presentation of colorectal cancer varies predictably based on tumour location, reflecting differences in luminal diameter, stool consistency, and biological behavior.

Right-Sided (Proximal) Colon Cancer

Typical Presentation: Insidious onset; often advanced at diagnosis

Cardinal Features:

• Iron deficiency anaemia (most common): Chronic occult bleeding from friable tumour surface
  • "Symptoms: Fatigue, exertional dyspnea, pallor, palpitations"
  • Often the only finding; may be profound (Hb less than 80 g/L)
• Abdominal mass: Palpable in right iliac fossa or right upper quadrant
  • Caecal tumours may grow large (> 10 cm) before causing symptoms
  • Non-tender, firm, may be mobile
• Weight loss: Catabolic state, reduced appetite, tumour metabolic demand
• Vague abdominal discomfort: Ill-defined, non-colicky pain
• Change in bowel habit: Less common than left-sided; may describe intermittent diarrhea

Infrequent: Frank obstruction (wide lumen rarely obstructs)

Red Flag: Unexplained iron deficiency anaemia in ANY adult (male or postmenopausal female) mandates bidirectional endoscopy (colonoscopy + OGD) to exclude GI malignancy.

Left-Sided (Distal) Colon Cancer

Typical Presentation: More symptomatic earlier; altered bowel habit predominates

Cardinal Features:

• Change in bowel habit: Persistent (> 6 weeks) alteration
  • Increased frequency of defecation
  • Looser stools or diarrhea
  • Alternating constipation and diarrhea
  • Feeling of incomplete evacuation
• Constipation: Progressive difficulty with bowel movements
  • May progress to subacute obstruction
• Abdominal pain: Colicky, left lower quadrant
  • Associated with bowel distension proximal to obstructing lesion
• Rectal bleeding: More overt than right-sided
  • Dark red blood mixed with stool
  • Differentiate from hemorrhoids (bright red, on surface, after defecation)
• Tenesmus: Sensation of rectal fullness, urge to defecate without result
• Pencil-thin stools: "Ribbon stools" from luminal narrowing

Acute Presentation: Large bowel obstruction (15-20% of left-sided CRC)

• Abdominal distension, colicky pain, vomiting (late), absolute constipation
• Requires urgent surgical management

Rectal Cancer

Typical Presentation: Rectal bleeding most prominent; local symptoms

Cardinal Features:

• Fresh rectal bleeding: Bright red blood
  • Often attributed to hemorrhoids, delaying diagnosis
  • May be mixed with stool or coating surface
• Mucus per rectum: Excessive rectal mucin production
• Tenesmus: Constant urge to defecate, sensation of incomplete evacuation
• Change in bowel habit: Increased frequency, urgency, loose stools
• Rectal pain: Indicates advanced local disease
  • Perineural invasion, invasion of pelvic floor
  • Continuous, deep pelvic pain
  • Pain is NOT a feature of early rectal cancer (rectum lacks somatic innervation)
• Palpable rectal mass: Digital rectal examination essential

Advanced Local Disease:

• Bladder involvement: Pneumaturia, fecaluria (colovesical fistula), recurrent UTI
• Vaginal involvement: Rectovaginal fistula (feculent vaginal discharge)
• Sacral invasion: Severe pain, sciatica

Red Flag Symptoms Requiring 2-Week Wait Referral (UK)

NICE Guidelines (NG12) specify suspected cancer referral criteria:

[!CAUTION] Urgent Referral for Suspected Colorectal Cancer (2-Week Wait)

Adults aged ≥40 years:

• Unexplained weight loss AND abdominal pain
• Aged ≥50 years with unexplained rectal bleeding
• Aged ≥60 years with iron deficiency anaemia OR change in bowel habit (> 6 weeks)
• Positive FIT result (≥10 μg Hb/g faeces)

Palpable Findings:

• Rectal or abdominal mass (any age)

Consider Urgent Referral (clinical judgment):

• Aged less than 50 years with rectal bleeding AND any of:
  • Abdominal pain
  • Change in bowel habit
  • Weight loss
  • Iron deficiency anaemia

FIT Testing in Primary Care: For patients with low-risk but not no-risk symptoms (e.g., abdominal pain without mass, change in bowel habit in less than 60-year-old), quantitative FIT can risk-stratify and guide referral. Threshold ≥10 μg Hb/g faeces triggers 2-week wait referral.

Physical Examination Findings

General Inspection

• Cachexia: Advanced disease, malnutrition
• Pallor: Anaemia (conjunctival, palmar)
• Jaundice: Liver metastases with biliary obstruction
• Lymphadenopathy: Virchow's node (left supraclavicular) indicates metastatic disease

Abdominal Examination

Inspection:

• Distension (bowel obstruction)
• Visible peristalsis (obstruction proximal to competent ileocaecal valve)
• Surgical scars (previous resection)

Palpation:

• Right iliac fossa mass: Caecal or ascending colon tumour
  • Firm, non-tender, may be mobile or fixed
• Hepatomegaly: Irregular, nodular liver edge suggests metastases
  • May have associated ascites
• Peritoneal carcinomatosis: Diffuse nodularity, omental cake (epigastric mass)

Percussion:

• Ascites (shifting dullness): Peritoneal metastases or hypoalbuminaemia

Auscultation:

• High-pitched tinkling bowel sounds (obstruction)
• Absence of bowel sounds (perforation, ileus)

Digital Rectal Examination (DRE)

Essential for ALL patients with suspected colorectal cancer.

Technique: Inspect perianal region → lubricated gloved finger gently inserted → palpate anteriorly, posteriorly, circumferentially

Assess:

• Mass presence: 60-70% of rectal cancers palpable on DRE
• Location: Anterior, posterior, lateral wall; distance from anal verge
• Size: Estimate circumferential extent (1/3, 1/2, circumferential)
• Mobility: Mobile vs fixed to pelvic structures
  • Fixed mass suggests T4 disease (invasion of prostate, vagina, sacrum)
• Sphincter tone: Reduced if invasion of pelvic floor

Findings:

• Firm, irregular, ulcerated mass
• Blood and/or mucus on examining finger

Note: Normal DRE does NOT exclude colorectal cancer (limited to distal 8-10 cm).

Modes of Presentation

Emergency Presentations (associated with worse prognosis):

• Large bowel obstruction (15-20%): Left-sided tumours, acute presentation requiring surgical decompression or stenting
• Perforation (3-5%): Free perforation (generalized peritonitis, septic shock) or contained perforation (localized abscess)
• Massive hemorrhage (less than 1%): Rarely presents with hemodynamic instability requiring transfusion

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5. Investigations

Diagnostic Algorithm

SUSPECTED COLORECTAL CANCER
           ↓
┌──────────────────────────┐
│ PRIMARY CARE ASSESSMENT  │
├──────────────────────────┤
│ • History & Examination  │
│ • FBC (anaemia check)    │
│ • FIT if low-risk sx     │
└──────────────────────────┘
           ↓
     Meets 2WW criteria?
           ↓
    YES ──────────→ 2-WEEK WAIT REFERRAL
           ↓
┌──────────────────────────┐
│  SECONDARY CARE          │
├──────────────────────────┤
│ • Colonoscopy + Biopsy   │
│   (Gold standard)        │
│ • CT Colonography if     │
│   colonoscopy incomplete │
└──────────────────────────┘
           ↓
    DIAGNOSIS CONFIRMED
           ↓
┌──────────────────────────┐
│ STAGING INVESTIGATIONS   │
├──────────────────────────┤
│ COLON CANCER:            │
│ • CT Chest-Abdomen-Pelvis│
│ • CEA                    │
│                          │
│ RECTAL CANCER:           │
│ • CT CAP                 │
│ • MRI Pelvis (essential) │
│ • CEA                    │
└──────────────────────────┘
           ↓
      MDT DISCUSSION

Initial Investigations (Primary Care / Emergency Department)

CEA (Carcinoembryonic Antigen):[18]

• Glycoprotein tumour marker; elevated in 60-70% of CRCs
• NOT diagnostic (lacks sensitivity/specificity for screening or diagnosis)
• Utility: Baseline pre-treatment value prognostic; serial monitoring detects recurrence post-resection
• Elevated in benign conditions: smoking, cirrhosis, IBD, pancreatitis
• Reference range: less than 3 ng/mL (non-smokers), less than 5 ng/mL (smokers)

FIT Testing:

• Immunochemical detection of human globin (specific, no dietary restriction needed)
• Sensitivity for CRC: 79% (95% CI 69-86%)
• Specificity for CRC: 94% (95% CI 92-95%)
• Positive predictive value: ~5-10% (depends on pre-test probability)
• Threshold of ≥10 μg Hb/g faeces triggers 2-week wait referral in NHS
• Higher thresholds (≥40, ≥150) stratify for colonoscopy urgency

Diagnostic Investigations

Colonoscopy

Gold Standard for CRC diagnosis and polyp surveillance.[19]

Advantages:

• Complete visualization of entire colon (> 95% completion rate)
• Tissue biopsy for histological diagnosis (essential)
• Polypectomy of synchronous lesions (present in 30% of CRC patients)
• Therapeutic intervention (stenting, tattooing)

Technique:

• Bowel preparation (polyethylene glycol or sodium picosulfate) required for adequate visualization
• Sedation (midazolam ± fentanyl) or unsedated with Entonox
• Insertion to caecum confirmed by visualization of ileocaecal valve, appendiceal orifice, tri-radiate folds
• Withdrawal time ≥6 minutes (quality metric for polyp detection)

Findings in CRC:

• Polypoid mass, ulcerated lesion, stricturing lesion
• Biopsy for histology (adenocarcinoma, grade, subtype)
• Tattooing: India ink injected submucosally 3-5 cm distal to lesion to mark site for surgical resection

Complications (rare):

• Perforation (0.1-0.2%)
• Bleeding post-polypectomy (0.3-0.6%)
• Cardiovascular events (sedation-related)
• Incomplete examination (10-15%): challenging anatomy, poor preparation, obstructing lesion

Incomplete Colonoscopy: If tumour occludes lumen preventing proximal examination, CT colonography required to exclude synchronous proximal lesion.

CT Colonography (CTC)

Virtual colonoscopy using multidetector CT with 3D reconstruction.

Indications:

• Incomplete colonoscopy (obstructing tumour, difficult anatomy)
• Contraindication to colonoscopy (comorbidity, anticoagulation)
• Screening in selected populations (patient preference, frailty)

Technique:

• Bowel preparation (same as colonoscopy)
• Insufflation of colon with CO₂ or room air via rectal catheter
• Prone and supine acquisitions
• Sensitivity for polyps > 10 mm: 90%, for CRC: > 95%

Limitations:

• No biopsy capability (requires subsequent colonoscopy if lesion detected)
• Flat lesions missed
• Radiation exposure (~5-10 mSv)
• Cannot remove polyps

Flexible Sigmoidoscopy

Limited examination to 60 cm (rectum, sigmoid, descending colon).

Indications:

• Suspected rectal/sigmoid cancer requiring rapid diagnosis
• Bowel cancer screening in some programmes (once-only FS at age 55)
• Frail patients unable to tolerate full colonoscopy

Limitations: Misses proximal (right-sided) lesions — approximately 40% of CRCs.

Staging Investigations

Staging determines prognosis and treatment strategy. TNM (AJCC 8th Edition) staging requires assessment of primary tumour (T), regional lymph nodes (N), and distant metastases (M).[6]

CT Chest-Abdomen-Pelvis (CT CAP)

Standard staging investigation for ALL colorectal cancers.

Protocol: Intravenous contrast-enhanced multidetector CT

• Chest CT: Lung metastases (40% of metastatic disease)
• Abdominal CT: Liver metastases (most common, 50-70%), nodal disease, primary tumour assessment
• Pelvic CT: For colon cancer; INSUFFICIENT for rectal cancer local staging

Assessment:

• Primary tumour: Size, location, extramural extension
  • Limited accuracy for T staging (~65-75%)
• Lymph nodes: Size, morphology
  • Node > 10mm short axis suspicious but not diagnostic
• Liver: Metastases appear as hypodense lesions; number, size, location (segmental anatomy)
• Lung: Nodules > 10mm suspicious; less than 5mm likely benign
• Peritoneum: Ascites, omental cake, peritoneal nodules
• Other: Bone metastases (rare), adrenal, ovarian

Limitations:

• Cannot reliably differentiate T3 from T4a
• Nodal staging based on size (sensitivity/specificity ~60-70%)
• Small liver metastases (less than 10mm) may be missed

MRI Pelvis (Rectal Cancer)

MANDATORY for all rectal cancers (tumour less than 15 cm from anal verge).[6]

High-resolution MRI provides superior soft tissue contrast for local staging, critically informing neoadjuvant treatment decisions.

Protocol:

• T2-weighted sequences in axial, sagittal, coronal planes
• Thin slices (3mm) perpendicular to tumour axis
• No bowel preparation required
• Small field-of-view focused on pelvis

Key Assessment Parameters:

1. Tumour Height from Anal Verge

• Measured in sagittal plane
• Determines surgical approach (anterior resection vs abdominoperineal resection)
• Low rectal (less than 5cm), mid rectal (5-10cm), upper rectal (10-15cm)

2. T Stage (Depth of Invasion)

• T1: Submucosa
• T2: Muscularis propria
• T3: Into mesorectal fat
  • "T3 subcategory: Extent of extramural spread measured (T3a less than 1mm, T3b 1-5mm, T3c 5-15mm, T3d > 15mm)"
  • Deeper invasion (T3c/d) = worse prognosis
• T4 a: Visceral peritoneum
• T4 b: Adjacent organs (prostate, seminal vesicles, uterus, vagina, bladder, pelvic sidewall, sacrum)

3. Circumferential Resection Margin (CRM)[6]

• Most critical prognostic factor for local recurrence
• Shortest distance from tumour (or tumour deposit/lymph node) to mesorectal fascia (surgical resection plane in TME)
• CRM positive/threatened: less than 1mm from mesorectal fascia
• CRM negative: ≥1mm from mesorectal fascia
• CRM involvement predicts R1 resection and local recurrence; mandates neoadjuvant chemoradiotherapy

4. Extramural Vascular Invasion (EMVI)

• Tumour invasion into extramural veins (beyond muscularis propria)
• Strong independent predictor of distant metastases and poor prognosis
• Graded: mrEMVI negative, mrEMVI positive (score 1-4 based on extent)
• Presence influences adjuvant chemotherapy decisions

5. Nodal Involvement

• Mixed signal intensity, irregular border, size > 8-9mm
• Mesorectal vs lateral pelvic (internal iliac) nodes
• Lateral pelvic nodes: Outside mesorectal envelope; if enlarged, consider extended lymphadenectomy

6. Relationship to Adjacent Structures

• Levator ani muscles, anal sphincter complex, intersphincteric plane
• Determines sphincter preservation feasibility

MRI Restaging: Repeated 6-8 weeks post-neoadjuvant chemoradiotherapy to assess response (yT, yN staging) and surgical planning.

Endorectal Ultrasound (EUS)

Use: Early rectal cancer (T1-T2) assessment to determine suitability for local excision.

Advantages:

• Superior T1 vs T2 differentiation (85-90% accuracy)
• Assesses depth of submucosal invasion (sm1, sm2, sm3)

Limitations:

• Operator-dependent
• Cannot assess CRM
• Difficult with stenotic lesions

Clinical Application: T1 sm1 tumours with favorable features (well-differentiated, no lymphovascular invasion, less than 3cm) may be suitable for transanal endoscopic microsurgery (TEM) instead of radical surgery.

PET-CT

NOT routine for primary staging.

Indications:

• Oligometastatic disease: Confirm isolated liver/lung metastases prior to curative metastasectomy
• Recurrent disease: Suspected recurrence with rising CEA but negative CT
• Equivocal liver lesions: Characterize indeterminate lesions on CT/MRI
• Radiotherapy planning: Define biological tumour volume

Limitations:

• Expensive, limited availability
• False positives: Inflammation, infection, benign lesions
• False negatives: Small metastases, mucinous tumours (low FDG avidity)

Tumour Markers

CEA (Carcinoembryonic Antigen):[18]

• Measured pre-operatively as baseline
• Post-operative rise (> 25% above baseline or above normal range) suggests recurrence
• Surveillance: Measured 3-monthly for 3 years, then 6-monthly for 2 years
• Rising CEA should prompt CT CAP to detect recurrence

Histopathological Assessment

Biopsy Diagnosis (pre-operative):

• Adenocarcinoma (> 90%)
• Grading: Well-differentiated (G1), moderately differentiated (G2), poorly differentiated (G3)
• Special subtypes: Mucinous (> 50% mucin), signet-ring cell, medullary, adenosquamous

Surgical Specimen Reporting (post-operative, synoptic reporting):

Macroscopic:

• Tumour size, location
• Distance to resection margins (proximal, distal, radial/CRM)
• Quality of mesorectal excision (rectal only): Complete, nearly complete, incomplete

Microscopic:

• T stage: Depth of invasion (pT1-pT4)
• N stage: Number of positive lymph nodes / total nodes examined (minimum ≥12 required for adequate staging)
• Lymphovascular invasion (LVI): Present/absent (adverse prognostic factor)
• Perineural invasion (PNI): Present/absent (adverse prognostic factor)
• Tumour budding: High-grade budding (≥10 buds) associated with worse prognosis
• CRM: Positive (less than 1mm) vs negative (≥1mm) — critical for rectal cancer
• Resection margin status: R0 (clear margins), R1 (microscopic involvement), R2 (macroscopic residual)

Molecular Testing (on all newly diagnosed CRCs):[12]

• Mismatch Repair (MMR) IHC: MLH1, MSH2, MSH6, PMS2 expression
  • Loss of expression → dMMR → consider Lynch syndrome
  • "Sporadic MLH1 loss: Reflex BRAF V600E or MLH1 promoter methylation testing"
• RAS mutation testing (KRAS exons 2, 3, 4; NRAS exons 2, 3, 4): Determines anti-EGFR therapy eligibility (only effective in RAS wild-type)[20]
• BRAF V600E mutation: Prognostic (poor if present in RAS wild-type, metastatic disease); excludes Lynch syndrome if MLH1-deficient
• HER2 amplification (metastatic setting): Emerging target (trastuzumab/pertuzumab in RAS/BRAF wild-type, HER2-positive)

TNM Staging (AJCC 8th Edition)

T Stage (Primary Tumour):

• Tis: Carcinoma in situ (intraepithelial or intramucosal)
• T1: Submucosa
• T2: Muscularis propria
• T3: Subserosa or non-peritonealized pericolic/perirectal tissues
• T4a: Penetrates visceral peritoneum
• T4b: Directly invades other organs or structures

N Stage (Regional Lymph Nodes):

• N0: No regional lymph node metastasis
• N1a: 1 regional lymph node
• N1b: 2-3 regional lymph nodes
• N1c: Tumour deposits (satellite nodules) without lymph node metastasis
• N2a: 4-6 regional lymph nodes
• N2b: ≥7 regional lymph nodes

M Stage (Distant Metastasis):

• M0: No distant metastasis
• M1a: One organ/site (liver, lung, ovary, non-regional lymph nodes)
• M1b: More than one organ/site
• M1c: Peritoneal metastasis ± other sites

Stage Grouping:

---

6. Management

Colorectal cancer management is complex, stage-dependent, and requires coordinated multidisciplinary team (MDT) input involving colorectal surgeons, medical oncologists, radiation oncologists, radiologists, pathologists, and specialist nurses.

Principles of Management

1. MDT Discussion: All cases discussed at colorectal cancer MDT meeting before treatment initiation
2. Curative Intent: Stages 0-III (and selected Stage IV oligometastatic)
3. Palliation: Stage IV with extensive metastases
4. Neoadjuvant Therapy: Rectal cancer T3/T4 or N+ requires pre-operative chemoradiotherapy or radiotherapy[7]
5. Surgery: Cornerstone of curative treatment for localized disease
6. Adjuvant Chemotherapy: Stage III (all), high-risk Stage II[10]
7. Molecular-Directed Therapy: RAS/BRAF/MSI status guides systemic treatment[8,20]

Management by Stage: Colon Cancer

Stage 0 (Tis — Carcinoma In Situ)

Treatment: Endoscopic resection (polypectomy or endoscopic mucosal resection)

Criteria for Adequate Endoscopic Treatment:

• Complete excision with clear margins
• Well-differentiated histology
• No lymphovascular invasion

Surveillance: Colonoscopy at 1 year, then 3 yearly

Stage I (T1-T2, N0, M0)

Treatment: Surgical resection ALONE (no adjuvant therapy required)

Surgical Approach:

• Right hemicolectomy: Caecal, ascending colon, hepatic flexure tumours
  • Ligation of ileocolic and right colic vessels at origin
  • Includes terminal ileum, caecum, ascending colon, proximal transverse colon
• Extended right hemicolectomy: Transverse colon tumours
  • Additional ligation of middle colic vessels
• Left hemicolectomy: Descending colon tumours
  • Ligation of left colic vessels
• Sigmoid colectomy: Sigmoid tumours
  • Ligation of sigmoid vessels; preservation of left colic artery
• Subtotal/total colectomy: Synchronous cancers, FAP, HNPCC

Oncological Principles:

• Adequate margins: ≥5 cm proximal and distal (except rectum where 2 cm distal acceptable)
• Lymphadenectomy: High vascular ligation at vessel origin; minimum 12 lymph nodes harvested for adequate staging[21]
• En bloc resection: If adherent to adjacent structures (even if inflammatory, not malignant)

Laparoscopic vs Open:

• Laparoscopic approach oncologically equivalent to open surgery[22]
• Benefits: Reduced pain, shorter hospital stay (median 5 vs 7 days), faster return of bowel function, improved cosmesis
• Long-term survival identical
• Contraindications: Locally advanced (T4b), emergency presentation (obstruction/perforation)

Prognosis: 5-year survival > 90%

Stage II (T3-T4, N0, M0)

Treatment: Surgical resection (same principles as Stage I)

Adjuvant Chemotherapy: NOT routine for standard-risk Stage II

High-Risk Features (consider adjuvant chemotherapy):[10]

• T4 tumour (particularly T4b with organ invasion)
• Inadequate lymph node harvest (less than 12 nodes examined)
• Poorly differentiated histology (G3)
• Lymphovascular invasion (LVI)
• Perineural invasion (PNI)
• Bowel obstruction or perforation at presentation
• Positive resection margin (R1)

Molecular Considerations:

• MSI-H Stage II: EXCELLENT prognosis; NO benefit from 5-FU adjuvant chemotherapy; observe
• MSS Stage II with high-risk features: Consider FOLFOX adjuvant therapy

Decision-Making: Individualized discussion balancing recurrence risk (~20-25% for high-risk Stage II) vs chemotherapy toxicity (neuropathy, myelosuppression). Multi-gene assays (Oncotype DX) may refine recurrence risk prediction.

Prognosis: 5-year survival 75-87% depending on T stage

Stage III (Any T, N1-N2, M0)

Treatment: Surgical resection + ADJUVANT CHEMOTHERAPY (standard of care)[10]

Adjuvant Chemotherapy Regimens:

FOLFOX (5-FU + Leucovorin + Oxaliplatin):

• Standard regimen based on MOSAIC trial[10]
• Schedule: mFOLFOX6 every 2 weeks
  • Oxaliplatin 85 mg/m² IV day 1
  • Leucovorin 400 mg/m² IV day 1
  • 5-FU 400 mg/m² IV bolus day 1, then 2400 mg/m² continuous infusion over 46 hours
• Duration: 3 months (low-risk Stage III: T1-3, N1) or 6 months (high-risk Stage III: T4 or N2) — based on IDEA collaboration meta-analysis[23]
• Benefit: 7.5% absolute improvement in 5-year disease-free survival vs 5-FU/LV alone[10]

CAPOX (Capecitabine + Oxaliplatin):

• Alternative to FOLFOX: Oral capecitabine replaces infusional 5-FU
• Schedule: 3-weekly cycles
  • Oxaliplatin 130 mg/m² IV day 1
  • Capecitabine 1000 mg/m² PO twice daily days 1-14
• Convenience: No central line required; preferred by some patients
• Efficacy: Non-inferior to FOLFOX

Capecitabine Monotherapy:

• Used in frail/elderly patients unable to tolerate oxaliplatin
• Lower efficacy than combination therapy

Timing: Initiate within 6-8 weeks post-surgery (earlier better; benefit diminishes if delayed > 12 weeks)

Toxicity Management:

• Oxaliplatin neuropathy: Cumulative, dose-limiting (> 70% experience some neuropathy)
  • Peripheral sensory neuropathy, cold-induced laryngopharyngeal dysesthesia
  • May necessitate dose reduction or omission of oxaliplatin
• Myelosuppression: Neutropenia (15-20%), thrombocytopenia
• Diarrhea: 5-FU/capecitabine-related; may require dose reduction
• Hand-foot syndrome: Capecitabine-associated; painful erythema/desquamation of palms/soles

Prognosis: 5-year survival 44-83% depending on T and N stage

Stage IV (Any T, Any N, M1)

Principles:

• Metastatic disease generally INCURABLE (median survival 24-30 months with modern therapy)
• EXCEPTIONS: Selected oligometastatic disease amenable to metastasectomy (10-15% of Stage IV)
• Treatment goals: Prolong survival, maintain quality of life, palliate symptoms
• MDT discussion essential; consider hepatobiliary surgery involvement if liver metastases

Management Algorithm:

STAGE IV COLORECTAL CANCER
          ↓
┌─────────────────────────┐
│ ASSESS RESECTABILITY    │
└─────────────────────────┘
          ↓
     Oligometastatic?
     (≤4 lesions, liver/lung)
          ↓
    YES          NO
     ↓            ↓
Synchronous   Systemic
Resectable?   Chemotherapy
     ↓            ↓
 YES   NO    1st Line
  ↓     ↓        ↓
  ↓  Chemo  FOLFOX/FOLFIRI
  ↓  then   + Biologics
  ↓  Resect     ↓
  ↓     ↓   Progressive?
  ↓     ↓       ↓
  └─────┴───→ YES    NO
           ↓        ↓
        2nd Line Continue
        (Switch)    ↓
           ↓    Good Response?
        3rd Line    ↓
           ↓       YES
       Immunotherapy    ↓
       (if MSI-H)   Consider
           ↓     Metastasectomy
       Palliative
       Care

Resectable Metastatic Disease (Curative Intent):

Criteria for Resectability:

• ≤4 metastatic lesions (liver and/or lung)
• Technically resectable with clear margins (R0)
• Adequate future liver remnant (≥25-30% with normal liver, ≥40% with chemotherapy-damaged liver)
• Absence of unresectable extrahepatic disease
• Patient fit for major surgery

Approach:

• Synchronous resectable metastases:
  • "Option 1: Simultaneous colorectal and liver resection (if liver resection minor)"
  • "Option 2: Colorectal resection → 2-3 months chemotherapy → liver resection"
  • "Option 3: Liver-first approach (if primary asymptomatic)"
• Metachronous metastases (detected post-primary resection):
  • Chemotherapy (FOLFOX/FOLFIRI ± biologics) → reassess → metastasectomy if response/stable
• Conversion therapy: Initially unresectable made resectable by downsizing with chemotherapy (10-15% conversion rate)

Outcomes: 5-year survival 30-40% post-liver resection (vs less than 5% without resection)

Unresectable Metastatic Disease (Palliative Intent):

First-Line Systemic Therapy:[20]

Chemotherapy Backbone:

• FOLFOX (5-FU/leucovorin/oxaliplatin)
• FOLFIRI (5-FU/leucovorin/irinotecan)
  • Irinotecan 180 mg/m² IV day 1
  • Leucovorin 400 mg/m² IV day 1
  • 5-FU 400 mg/m² bolus + 2400 mg/m² infusion

Choice between FOLFOX and FOLFIRI based on:

• Patient factors (comorbidity, neuropathy risk, functional status)
• Tumour factors (RAS/BRAF status, sidedness)
• No survival difference between regimens in unselected populations

Targeted Biological Agents (added to chemotherapy):

Anti-VEGF: Bevacizumab[20]

• Mechanism: Monoclonal antibody blocking vascular endothelial growth factor
• Indication: Add to FOLFOX or FOLFIRI (any RAS status)
• Dose: 5 mg/kg IV every 2 weeks (or 7.5 mg/kg every 3 weeks)
• Benefit: Improved progression-free survival (PFS) +2-3 months; overall survival (OS) +4-5 months
• Toxicity: Hypertension (manage with ACE inhibitors), proteinuria, bleeding, thromboembolism, bowel perforation (less than 2%, increased risk in Crohn's)
• Contraindications: Recent surgery (less than 28 days), bowel perforation risk, uncontrolled hypertension

Anti-EGFR: Cetuximab or Panitumumab[20]

• Mechanism: Monoclonal antibodies blocking epidermal growth factor receptor
• Indication: LEFT-SIDED tumours + RAS WILD-TYPE + BRAF WILD-TYPE
  • NO benefit (and potential harm) if RAS mutant
  • LEFT-sided > right-sided (retrospective subgroup analyses show no benefit in right-sided with anti-EGFR)
• Dose:
  • "Cetuximab: 400 mg/m² loading, then 250 mg/m² weekly"
  • "Panitumumab: 6 mg/kg IV every 2 weeks"
• Benefit (RAS wild-type, left-sided): PFS +3-4 months; OS +4-6 months vs chemotherapy alone
• Toxicity: Acneiform rash (paradoxically correlates with response), diarrhea, hypomagnesemia, hypersensitivity reactions (cetuximab)

Choice of Biologic:

• RAS wild-type, left-sided: Anti-EGFR (cetuximab/panitumumab) + chemotherapy
• RAS mutant or right-sided: Bevacizumab + chemotherapy

Second-Line Therapy:

• Switch chemotherapy backbone (FOLFOX → FOLFIRI or vice versa)
• Continue or switch biologic (if not used in first-line, or switch bevacizumab to ramucirumab)
• FOLFIRI + Aflibercept: Anti-VEGF fusion protein; second-line option
• FOLFIRI + Ramucirumab: Anti-VEGFR2; alternative anti-angiogenic

Third-Line Therapy:

• Regorafenib: Oral multi-kinase inhibitor; approved for refractory metastatic CRC
• Trifluridine/tipiracil (TAS-102): Oral nucleoside analogue; modest survival benefit
• Fruquintinib: Anti-VEGFR tyrosine kinase inhibitor

Immunotherapy (MSI-H/dMMR tumours):[8]

First-Line (preferred for MSI-H):

• Pembrolizumab (anti-PD-1): KEYNOTE-177 trial demonstrated superior PFS vs chemotherapy in MSI-H/dMMR metastatic CRC[8]
  • "Dose: 200 mg IV every 3 weeks or 400 mg every 6 weeks"
  • "Response rate: 43% (vs 33% with chemotherapy)"
  • "Median PFS: 16.5 months (vs 8.2 months)"
  • Better toxicity profile than chemotherapy
• Nivolumab + Ipilimumab (anti-PD-1 + anti-CTLA-4): CheckMate-142 study showed 60% response rate
  • "Dose: Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg every 3 weeks × 4, then nivolumab alone"

Note: MSI-H accounts for 5% of metastatic CRC (lower than 15% in localized CRC due to better prognosis reducing metastatic progression). ALL metastatic CRCs should be tested for MSI/dMMR.

Palliative Primary Tumour Resection:

• NOT routinely recommended in asymptomatic patients (primary tumour resection does not improve survival in asymptomatic metastatic disease)
• Indications for resection/intervention:
  • "Obstruction: Stenting (if left-sided) or surgical bypass/resection"
  • "Perforation: Emergency resection"
  • "Massive bleeding: Endoscopic/angiographic control or resection"

Prognosis: Median survival 24-30 months with modern therapy (unresectable); 5-year survival ~14% overall, 30-40% if metastasectomy achieved

Management of Rectal Cancer

Rectal cancer (tumour less than 15 cm from anal verge) requires distinct management approach due to anatomical constraints, risk of local recurrence, and sphincter preservation considerations.[7]

Staging and Risk Stratification

MRI Pelvis mandatory for ALL rectal cancers (see Investigations section)

Risk Categories:

Low Risk (Good Prognosis):

• Early tumour (T1-T2)
• No nodal involvement (N0)
• No threatened CRM (> 2mm clearance)
• No EMVI
• → Primary surgery WITHOUT neoadjuvant therapy

Intermediate Risk:

• T3a-b (extramural extension less than 5mm), N0
• CRM clear
• No EMVI
• → Consider short-course radiotherapy OR primary surgery (individualized)

High Risk (Requires Neoadjuvant Therapy):

• T3c-d (extramural extension ≥5mm)
• T4 (adjacent organ invasion)
• N+ (nodal involvement)
• Threatened/involved CRM (less than 2mm)
• EMVI present
• → Neoadjuvant chemoradiotherapy OR short-course radiotherapy

Neoadjuvant Therapy for Locally Advanced Rectal Cancer[7]

Rationale: Downstage tumour, improve R0 resection rate, reduce local recurrence, potential sphincter preservation

Option 1: Long-Course Chemoradiotherapy (LC-CRT)

Protocol:

• Radiotherapy: 45-50.4 Gy in 25-28 fractions over 5 weeks to pelvis
• Concurrent Chemotherapy: Capecitabine 825 mg/m² PO twice daily during radiotherapy (radiosensitizer)
• Surgery: 8-12 weeks post-completion (allows tumour regression)

Indications:

• Locally advanced rectal cancer (T3c-d, T4, N+, threatened CRM)
• Desire for sphincter preservation (may downstage low tumour away from sphincter)

Outcomes:

• Pathological complete response (pCR): 15-20% (no viable tumour in resection specimen)
• Tumour downstaging: 60-70%
• Local recurrence reduction: From 10-15% to 5-10%
• Survival: No OS benefit vs surgery alone in initially resectable disease, but improved local control

Toxicity: Diarrhea, radiation proctitis, urinary symptoms, sexual dysfunction (30-40% males)

Option 2: Short-Course Radiotherapy (SC-RT)

Protocol:

• Radiotherapy: 25 Gy in 5 fractions over 1 week (Monday-Friday)
• Surgery: Within 1 week (traditional) OR delayed 8-12 weeks (allows downstaging, similar to LC-CRT)
• NO concurrent chemotherapy

Indications:

• Locally advanced rectal cancer (particularly if no desire for downsizing, e.g., upper rectal with adequate distal margin)
• Equivalent oncological outcomes to LC-CRT

Advantages: Shorter treatment time, no chemotherapy toxicity, cost-effective

Disadvantages: Less tumour downsizing if immediate surgery; late toxicity if immediate surgery

LC-CRT vs SC-RT: No survival difference; choice based on institutional preference, patient factors, and downsizing goals

Total Neoadjuvant Therapy (TNT): Emerging approach combining full-dose chemotherapy (FOLFOX/CAPOX) with radiotherapy before surgery (either induction or consolidation strategy). Increases pCR rate to 25-30% and may enable organ preservation (watch-and-wait) in select complete responders.

Surgical Management of Rectal Cancer

Total Mesorectal Excision (TME) — Surgical Gold Standard[11]

Principle: En bloc resection of rectum with entire mesorectal envelope (mesorectum = fatty tissue surrounding rectum containing lymphatics and vessels) by sharp dissection in avascular plane between mesorectal fascia and parietal pelvic fascia (holy plane).

Technique:

• Open, laparoscopic, or robotic approach (oncological equivalence if TME quality maintained)
• Mobilization of rectum posteriorly (presacral plane), laterally (lateral ligaments/stalks containing middle rectal vessels), anteriorly (Denonvilliers' fascia)
• High vascular ligation (IMA or high tie vs low tie preserving left colic artery — debate ongoing)
• Minimum 2 cm distal margin (1 cm acceptable if necessary for sphincter preservation post-neoadjuvant therapy)
• Circular stapled or handsewn colorectal/coloanal anastomosis

Quality Metrics:

• Mesorectal envelope: Complete (intact, smooth), nearly complete (less than 5mm defects), incomplete (defects to muscularis propria, irregular, coning) — complete in > 90% essential
• CRM: Negative (≥1mm)
• Lymph node yield: ≥12 nodes

Outcomes: Local recurrence less than 10% with TME (vs 30-40% pre-TME era)

Surgical Options:

1. Anterior Resection (AR)

• Indication: Upper/mid rectal cancer (> 5-6 cm from anal verge post-neoadjuvant therapy)
• Procedure: Resection of rectum with colorectal anastomosis (usually stapled)
• Sphincter: Preserved
• Stoma: Defunctioning loop ileostomy often formed to protect anastomosis (reversed 8-12 weeks later)

2. Low Anterior Resection (LAR)

• Indication: Low rectal cancer (2-5 cm from anal verge)
• Procedure: Resection with very low colorectal or coloanal anastomosis
• Sphincter: Preserved
• Anastomotic Leak Risk: Higher than AR (10-20% vs 3-5%)
• Functional Outcome: Low Anterior Resection Syndrome (LARS) common — urgency, frequency, incontinence, clustering (affects 50-80%)

3. Abdominoperineal Resection (APR)

• Indication: Very low rectal cancer (less than 2-3 cm from anal verge), anal sphincter involvement, inability to achieve clear distal margin
• Procedure: Resection of rectum, mesorectum, anal canal, and sphincter complex via combined abdominal and perineal approach
• Stoma: Permanent end colostomy
• Quality of Life: Stoma-related issues; higher perineal wound complications (20-30%)

4. Hartmann's Procedure

• Indication: Emergency setting (perforation, obstruction), unfit patients
• Procedure: Rectal resection, end colostomy, rectal stump oversewn or stapled
• Reversal: Difficult; many patients remain with permanent stoma

Local Excision (Selected T1 Tumours):

Transanal Endoscopic Microsurgery (TEM) / Transanal Minimally Invasive Surgery (TAMIS):

• Indication: T1 sm1, less than 3 cm, well/moderately differentiated, no lymphovascular invasion, less than 30% circumference, less than 10 cm from anal verge
• Procedure: Full-thickness excision of tumour via transanal approach
• Advantage: Avoids morbidity of TME, preserves sphincter
• Risk: Lymph node metastases in 10-15% T1 cancers (not addressed by local excision)
• Surveillance: Close follow-up; if adverse features on pathology (T1 sm2-3, LVI, poor differentiation, positive margin), completion TME recommended

Adjuvant Chemotherapy for Rectal Cancer

Stage III (ypN+ post-neoadjuvant therapy): Adjuvant chemotherapy recommended (FOLFOX or CAPOX, 3-6 months) — same as colon cancer

Stage II (ypT3-4, N0): Individualized; generally not routine if adequate neoadjuvant therapy completed

Note: Patients receiving neoadjuvant LC-CRT + surgery have already received some chemotherapy equivalent; total systemic therapy duration ~6 months including neoadjuvant.

Watch-and-Wait Strategy (Organ Preservation)

Concept: Patients achieving clinical complete response (cCR) after neoadjuvant chemoradiotherapy may be observed without immediate surgery, aiming to avoid operative morbidity and permanent stoma.

Criteria for Watch-and-Wait:

• Clinical complete response: No palpable tumour on DRE, normal endoscopy (may have scar/ulcer but no tumour), MRI showing no residual tumour (ymrT0)
• Informed patient accepting intensive surveillance and risk of regrowth
• Specialist center with expertise

Surveillance:

• DRE, endoscopy, MRI every 3 months year 1, then 6-monthly
• CEA monitoring

Outcomes:

• Sustained cCR: 80-85% at 3 years (i.e., 15-20% regrow, requiring salvage surgery)
• Salvage surgery: 95% successful with curative resection if regrowth detected early
• Survival: Non-inferior to immediate surgery in highly selected patients

Controversy: Oncological safety long-term still under investigation; not standard of care

---

7. Complications

Surgical Complications

Immediate/Early (less than 30 Days)

Anastomotic Leak: Most feared complication, associated with significant morbidity/mortality. Risk factors: Low rectal anastomosis, male sex, obesity, smoking, malnutrition, emergency surgery. Defunctioning ileostomy reduces clinical impact of leak but does not prevent it.

Late (> 30 Days)

LARS: Multifactorial (loss of rectal reservoir, sphincter damage, anastomotic level). No definitive cure; management includes dietary modification, loperamide, pelvic floor physiotherapy, sacral nerve stimulation (refractory cases).

Oncological Complications

Chemotherapy Toxicity

---

8. Prognosis & Outcomes

Survival by Stage

5-Year Overall Survival (SEER Database, US, 2012-2018):[9]

Stage-Specific Breakdown:

Note: Stage II heterogeneity (IIA vs IIC: 87% vs 58%) highlights importance of T4 substaging. Some Stage IIIA (T1-2, N1) have better prognosis than Stage IIB/C (T4, N0).

Prognostic Factors

Favourable Prognostic Factors

Adverse Prognostic Factors

Molecular Prognostic Markers

Recurrence Patterns

Overall Recurrence: 30-40% of Stage II-III CRC recurs despite curative-intent surgery ± adjuvant therapy

Sites:

• Liver: 50% of recurrences (most common site)
• Lung: 30-40%
• Local (pelvis for rectal): 10-15% (higher if no neoadjuvant therapy or poor TME quality)
• Peritoneum: 15-20%
• Distant lymph nodes: 10%
• Other: Bone, brain (less than 5% each)

Timing:

• 80% of recurrences occur within 2 years of surgery
• 95% within 5 years
• Surveillance most intensive in first 3 years

Surveillance Strategy

Goals: Detect recurrence early (when potentially resectable/curable) and identify metachronous polyps/cancers

NICE/ESMO Recommendations:

Years 1-3 (High-Risk Period):

• Clinical review + CEA: Every 3-6 months[18]
• CT CAP: 12-18 months post-surgery (detect asymptomatic liver/lung metastases)
• Colonoscopy: At 1 year (if pre-operative colonoscopy complete)

Years 4-5:

• Clinical review + CEA: Every 6 months
• CT CAP: Annually (if high-risk)

Beyond 5 Years:

• Colonoscopy surveillance: Continue based on polyp findings (every 3-5 years)
• Discharge from routine CRC surveillance if no recurrence by 5 years

Colonoscopy Surveillance (Metachronous Polyps/Cancers):

• 1 year: Detect missed synchronous lesions
• If negative: 3-5 yearly depending on polyp findings per BSG polyp surveillance guidelines

CEA Monitoring:[18]

• Rising CEA (≥25% above baseline or above upper limit normal) should prompt urgent CT CAP
• Sensitivity for recurrence: 60-70%
• False positives: Smoking, benign liver/lung disease

Factors Improving Outcomes Over Time

• Screening programmes: Stage migration toward earlier disease
• TME surgery: Reduced local recurrence from 30% to less than 10% in rectal cancer
• Neoadjuvant therapy: Improved R0 resection rates and local control
• Adjuvant chemotherapy (FOLFOX): 7.5% improvement in 5-year DFS for Stage III
• Targeted biologics: Bevacizumab, anti-EGFR agents extend survival in metastatic disease by 6-12 months
• Immunotherapy (MSI-H): Pembrolizumab first-line extends PFS from 8 to 16 months
• Liver/lung metastasectomy: 30-40% 5-year survival in selected oligometastatic patients

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9. Prevention & Screening

Primary Prevention

Modifiable Risk Factor Reduction:

Chemoprevention:

Aspirin:[16]

• Evidence: Regular use (≥5 years) associated with 20-30% CRC risk reduction in observational studies and RCTs
• Mechanism: COX inhibition, anti-platelet effects, anti-inflammatory
• USPSTF Recommendation (2016): Low-dose aspirin (75-100 mg daily) for CRC prevention in adults aged 50-59 with ≥10% 10-year cardiovascular risk, no bleeding risk, life expectancy > 10 years
• Benefit-Risk Balance: Cardiovascular benefit + CRC prevention vs bleeding risk
• Not universally recommended: Individualized decision

NSAIDs/COX-2 Inhibitors:

• Celecoxib reduces adenoma recurrence in FAP and sporadic adenoma patients
• Cardiovascular toxicity limits use for chemoprevention in average-risk population

Calcium and Vitamin D:

• Calcium supplementation (1200 mg/day) modestly reduces adenoma recurrence (~15%)
• Vitamin D: Observational data suggest benefit; RCTs inconclusive

Secondary Prevention (Screening)

Goal: Detect and remove premalignant polyps (adenomas) and identify early-stage cancer when curable

UK NHS Bowel Cancer Screening Programme[5]

Target Population:

• England/Wales/Northern Ireland: Ages 50-74 (expanded from 60-74 in 2021)
• Scotland: Ages 50-74

Screening Test: Faecal Immunochemical Test (FIT)

• Frequency: Every 2 years
• Method: Home stool sample kit; immunochemical detection of human hemoglobin
• Threshold: ≥10 μg Hb/g faeces → colonoscopy referral
• Uptake: ~65-70% (varies by region, socioeconomic factors)

Outcomes of FIT-Positive Individuals (NHS data):

• Cancer detected: 5-8%
• High-risk adenomas: 30-40%
• Low-risk adenomas: 20%
• Normal/low-risk findings: 40-50%

Impact:

• Mortality reduction: 16% in screened population (intention-to-treat analysis)[5]
• Stage migration: 55% of screen-detected cancers are Stage I (vs 25% symptomatically-detected)

One-Time Flexible Sigmoidoscopy (FS):

• Previously offered at age 55 in some UK regions (not universally)
• Detects and removes distal polyps
• 26% reduction in CRC incidence, 30% reduction in mortality (distal CRC only)
• Resource-intensive; FIT-based screening now prioritized

International Screening Approaches

USA (USPSTF 2021 Guidelines):

• Age: 45-75 years (lowered from 50 due to rising early-onset CRC)
• Options (patient choice):
  • Annual FIT or high-sensitivity guaiac fecal occult blood test (gFOBT)
  • FIT-DNA (Cologuard) every 1-3 years
  • Colonoscopy every 10 years
  • Flexible sigmoidoscopy every 5 years
  • CT colonography every 5 years

Australia:

• National Bowel Cancer Screening Program: Ages 50-74, biennial FIT
• Gradually expanding to 2-yearly invitations (currently phased by age)

Europe:

• Many countries implement FIT-based screening (Netherlands, Spain, Italy, France)
• Age ranges vary (50-74 typical)

High-Risk Surveillance

Individuals with elevated CRC risk require more intensive surveillance than population screening.

Lynch Syndrome (HNPCC)[12]

Surveillance:

• Colonoscopy: Every 1-2 years starting age 25 (or 5 years before youngest affected family member)
• Aspirin chemoprevention: 600 mg daily reduces CRC incidence by 60% (CAPP2 trial)
• Gynecological surveillance (females): Annual endometrial biopsy, transvaginal ultrasound starting age 30-35
• Upper GI surveillance: OGD every 2-3 years starting age 40 (gastric cancer risk)

Risk-Reducing Surgery:

• Prophylactic colectomy: Consider in FAP, not routine in Lynch syndrome
• Prophylactic hysterectomy/BSO: Discuss at age 40 or completion of childbearing (endometrial/ovarian cancer risk)

Familial Adenomatous Polyposis (FAP)

Surveillance:

• Genetic testing: Identify APC mutation in index case; test at-risk family members
• Colonoscopy/Flexible sigmoidoscopy: Annually starting age 10-15 (detect polyps)
• Prophylactic colectomy: Recommended late teens/early 20s (100% cancer risk)
  • "Options: Total proctocolectomy with ileal pouch-anal anastomosis (IPAA), or subtotal colectomy with ileorectal anastomosis (IRA) + rectal surveillance"
• Upper GI surveillance: OGD every 1-3 years (duodenal adenomas/ampullary cancer risk)

Attenuated FAP (aFAP): Later polyp onset, fewer polyps; colonoscopy every 1-2 years starting late teens; prophylactic colectomy in 30s-40s

Inflammatory Bowel Disease[15]

Surveillance Colonoscopy (British Society of Gastroenterology Guidelines):

• Start: 8-10 years after symptom onset (UC/Crohn's colitis)
• Frequency:
  • "High-risk (PSC, extensive inflammation, FH CRC, stricture): Annually"
  • "Intermediate-risk (post-inflammatory polyps, mild/moderate active inflammation): 2-3 yearly"
  • "Low-risk (limited extent, quiescent): 5 yearly"
• Technique: High-definition white light or chromoendoscopy with targeted biopsies of visible lesions

Family History of CRC

Risk Stratification:

FDR: First-degree relative (parent, sibling, child); SDR: Second-degree relative (grandparent, aunt/uncle)

Post-Polypectomy Surveillance

British Society of Gastroenterology Polyp Surveillance Guidelines:

Serrated Polyps:

• Sessile serrated lesions (SSL): Follow adenoma guidelines based on size/dysplasia
• Large SSL (≥10mm) or with dysplasia: 3-year surveillance

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10. References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660

2. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-767. doi:10.1016/0092-8674(90)90186-i

3. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66(4):683-691. doi:10.1136/gutjnl-2015-310912

4. Bouvard V, Loomis D, Guyton KZ, et al. Carcinogenicity of consumption of red and processed meat. Lancet Oncol. 2015;16(16):1599-1600. doi:10.1016/S1470-2045(15)00444-1

5. Atkin W, Wooldrage K, Parkin DM, et al. Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trial. Lancet. 2017;389(10076):1299-1311. doi:10.1016/S0140-6736(17)30396-3

6. Beets-Tan RGH, Lambregts DMJ, Maas M, et al. Magnetic resonance imaging for clinical management of rectal cancer: Updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol. 2018;28(4):1465-1475. doi:10.1007/s00330-017-5026-2

7. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731-1740. doi:10.1056/NEJMoa040694

8. André T, Shiu KK, Kim TW, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020;383(23):2207-2218. doi:10.1056/NEJMoa2017699

9. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-164. doi:10.3322/caac.21601

10. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343-2351. doi:10.1056/NEJMoa032709

11. Heald RJ, Husband EM, Ryall RD. The mesorectum in rectal cancer surgery--the clue to pelvic recurrence? Br J Surg. 1982;69(10):613-616. doi:10.1002/bjs.1800691019

12. Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895-2015. Nat Rev Cancer. 2015;15(3):181-194. doi:10.1038/nrc3878

13. Siegel RL, Jakobsen KK, Frederiksen BL, et al. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73(3):233-254. doi:10.3322/caac.21772

14. Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer. 2006;42(2):216-227. doi:10.1016/j.ejca.2005.09.023

15. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48(4):526-535. doi:10.1136/gut.48.4.526

16. Bibbins-Domingo K, US Preventive Services Task Force. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164(12):836-845. doi:10.7326/M16-0577

17. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50(1):113-130. doi:10.1111/j.1365-2559.2006.02549.x

18. Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24(33):5313-5327. doi:10.1200/JCO.2006.08.2644

19. Rex DK, Schoenfeld PS, Cohen J, et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2015;81(1):31-53. doi:10.1016/j.gie.2014.07.058

20. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386-1422. doi:10.1093/annonc/mdw235

21. Tsikitis VL, Larson DW, Huebner M, Lohse CM, Thompson PA. Predictors of recurrence free survival for patients with stage II and III colon cancer. BMC Cancer. 2014;14:336. doi:10.1186/1471-2407-14-336

22. Clinical Outcomes of Surgical Therapy Study Group. A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med. 2004;350(20):2050-2059. doi:10.1056/NEJMoa032651

23. Grothey A, Sobrero AF, Shields AF, et al. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med. 2018;378(13):1177-1188. doi:10.1056/NEJMoa1713709

24. Hashiguchi Y, Muro K, Saito Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol. 2020;25(1):1-42. doi:10.1007/s10147-019-01485-z

25. Engstrom PF, Arnoletti JP, Benson AB, et al. NCCN Clinical Practice Guidelines in Oncology: colon cancer. J Natl Compr Canc Netw. 2009;7(8):778-831. doi:10.6004/jnccn.2009.0056

26. Glynne-Jones R, Wyrwicz L, Tiret E, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv22-iv40. doi:10.1093/annonc/mdx224

27. National Institute for Health and Care Excellence. Colorectal cancer (NG151). Published January 29, 2020. Accessed January 6, 2026. https://www.nice.org.uk/guidance/ng151

28. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350-1356. doi:10.1038/nm.3967

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11. Patient Education & Layperson Explanation

What is Bowel Cancer?

Bowel cancer (also called colorectal cancer or CRC) is a cancer that develops in the large intestine (colon) or the back passage (rectum). It usually starts as a small growth called a polyp, which over many years can turn into cancer if not removed.

How Common Is It?

Bowel cancer is very common — it's the 4th most common cancer in the UK, with about 42,000 people diagnosed each year. It mainly affects older adults (most people diagnosed are over 60), but younger people can get it too.

What Causes It?

The exact cause isn't always known, but certain things increase your risk:

• Getting older (most common over age 50)
• Family history (parent, brother, or sister with bowel cancer)
• Diet high in red or processed meat (bacon, sausages, ham)
• Being overweight or obese
• Not exercising enough
• Smoking and drinking too much alcohol
• Inflammatory bowel disease (Crohn's disease, ulcerative colitis)

What Are the Symptoms?

See your GP if you have any of these for 3 weeks or more:

• Blood in your poo or bleeding from your bottom
• Change in bowel habit — going more often, looser poo, or constipation
• Tummy pain or bloating that doesn't go away
• Feeling very tired (from anaemia — low iron)
• Unexplained weight loss

Don't be embarrassed — these symptoms are common and usually NOT cancer, but it's important to get checked.

Can It Be Prevented?

Yes — you can lower your risk:

• Eat less red and processed meat (no more than 70g per day)
• Eat more fibre (vegetables, fruit, whole grains)
• Stay active (aim for 30 minutes exercise most days)
• Maintain a healthy weight
• Don't smoke and drink less alcohol
• Attend bowel cancer screening when invited

Bowel Cancer Screening

Who: Everyone aged 50-74 in England, Wales, Scotland, Northern Ireland

What: Home stool test kit (called FIT) sent every 2 years. You collect a small poo sample and post it back.

Why: The test can find tiny amounts of blood that you can't see. If positive, you'll be offered a colonoscopy (camera test) to check for polyps or cancer.

Does it work? YES — screening saves lives. It finds cancer early when treatment is more likely to cure it, and can find polyps before they turn into cancer.

How Is It Diagnosed?

If you have symptoms or a positive screening test, you'll be referred for a colonoscopy — a camera passed into your bowel to look for cancer or polyps. If anything suspicious is seen, a small sample (biopsy) is taken and checked under a microscope.

How Is It Treated?

Treatment depends on the stage (how far the cancer has spread):

Surgery (main treatment):

• The part of the bowel with the cancer is removed
• Most people recover well and don't need a permanent colostomy bag (though some do)

Chemotherapy:

• Often given after surgery if the cancer has spread to lymph nodes
• Kills any remaining cancer cells

Radiotherapy (mainly for rectal cancer):

• Often given before surgery to shrink the tumour

Advanced cancer:

• If the cancer has spread to other parts of the body (like the liver or lungs), treatment may include chemotherapy, targeted drugs, or immunotherapy to control the cancer and manage symptoms

What Are the Chances of Cure?

It depends on how early it's found:

• Early stage (cancer hasn't spread): More than 9 out of 10 people are cured
• Advanced stage (spread to lymph nodes): About 6-7 out of 10 are cured
• Spread to liver/lungs: Harder to cure, but treatment can help you live longer

This is why screening and early symptoms matter so much.

Living with and After Bowel Cancer

• Follow-up: You'll have regular check-ups, blood tests, and scans for 5 years
• Colonoscopy: You'll need regular colonoscopies to check for new polyps
• Lifestyle: Eating well, staying active, and not smoking help recovery and lower the chance of cancer coming back
• Support: Bowel Cancer UK and Macmillan Cancer Support offer information, advice, and support groups

Key Takeaway

Bowel cancer is common but very treatable, especially if caught early. Don't ignore symptoms — see your GP. Do your screening test when invited — it could save your life.

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Last Reviewed: 2026-01-06 | MedVellum Editorial Team

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.